Velo-cardio-facial syndrome (VCFS) is a autosomal dominant disorder. Patients with this disorder have a spectrum of abnormalities which include: cleft palate, speech and learning disabilities, typical facial appearances and cardiac defects. Our cytogenetic and molecular analysis of a group of VCFS patients provides insights into its genetic basis. Submicroscopic deletion of 22q11 have been found in approximately 90% of patients studied. Our findings support the use of molecular or molecular-cytogenetic analysis for the diagnosis of patients with VCFS. However, understanding the pathogenesis of this disorder will require identification of the deleted genes and investigations into the role that these genes play in normal embryonic and postnatal development. Finally, the role of the specific genes in the developing embryo can be manipulated in a mouse model to determine the developmental etiology of VCFS. Hence, a consortium of experienced basic scientists and clinical investigators at the Children's Hosp. of Phila, Wistar Institute, the Children's Seashore House, the Univs. of Penna. and Oklahoma have established a program dedicated to a multidisciplinary clinical and laboratory-based investigation of VCFS. The latest technologies in molecular genetics, clinical genetics, developmental biology and physical diagnosis will be applied to this syndrome. Thus, Project 1 will pursue several molecular approaches directed at gene identification (cDNA capture and exon prediction from DNA sequence). Project 2 will examine these genes in the developing mouse embryo to determine temporal and spatial expression during development (mouse embryo culture system). Using the molecular-diagnostic and screening tests (PCR and fluorescence in situ hybridization) which will be developed and applied by Project 3, a coordinated approach, combining comprehensive physical examination and laboratory-based testing will improve the specificity of diagnosis. This will result in the development of objective phenotypic criteria which will aid clinicians in recognizing at risk patients. Early diagnosis of VCFS will allow timely intervention to optimize speech and language development and to avoid some of the stigmata encountered as a result of defective communication skills. This program represents a team effort aimed at: molecular characterization of the deleted region 22q11 in VCFS, identification of the significant genes responsible for the VCFS phenotype and examination of the role that these genes play in normal and abnormal development.